1. Field of the Invention:
This invention relates to homogeneous membranes composed of acrylic copolymers that are useful in the fabrication of biosensors intended for in vitro use, particularly glucose sensors.
2. Background of the Invention:
Monitoring of many physiological parameters of medical significance is performed in clinical chemistry laboratories which are remote from the patient. Because of the time delay involved, the information obtained is historical and may not reflect the current state of the patient. As a consequence, many researchers are attempting to develop biosensors to be used in vivo which would provide real time data for a number of analytes of clinical importance. An excellent summary of current research in this area has been published by Collison and Meyerhoff (Analvtical Chemistry, 62, 425-437, 1990).
A primary requirement of such sensors is that they be compatible with the body. At a minimum, the materials used to fabricate the sensor must not exert any toxic or allergic effects on the body. In addition, sensors intended to be used in contact with blood must not provoke a thrombotic reaction. Few polymer materials can meet the stringent requirements of medical applications. Vadgama (Sensors and Actuators. B1, Nos. 1-6, 1-7, 1990) has summarized the problems involved with interfacing a biosensor with the biological environment.
A second requirement for biosensors intended for in vivo use is that the sensing element must exist in a stable environment. If the environment that the sensing element is exposed to is constantly changing, the sensor will experience "drift", and the values returned by the sensor will be in error. Thus, the sensing element must be "protected" in some way from the harsh biological environment. This is generally accomplished by interfacing a membrane between the sensing element and its environment. Such membranes must be biocompatible or the reaction of the body, e.g., thrombosis or an inflammatory reaction, will result in a continuing perturbation of the environment to which the sensing element is exposed. Thus, biocompatibility of membranes used in the fabrication of biosensors is necessary not only for reasons of safety, but also in order for the sensor to function at all. Wilkins and Radford (Biosensors & Bioelectronics. 5, No. 3, 167-213, 1990) have examined these issues for several biomaterials.
A final requirement, obviously, is that the sensor must accurately measure the analyte of interest. The sensing element is potentially exposed to body proteins, electrolytes, medication being administered to the patient, etc., any or all of which may interfere with the measurement. Membranes, then, must not only be biocompatible, but they must allow for accurate detection of the analyte of interest in the presence of a number of chemical entities. Thus, permeability properties must be matched to the design of the sensor as well as the analyte being measured.
Considerable research is currently being directed toward the development of an in vivo glucose sensor. Such a sensor would make it possible to continuously monitor a patient's blood glucose levels and allow the physician to develop therapy tailored to the individual. Most research in this area is devoted to the development of electroenzymatic sensors. Such sensors are simpler and less expensive to fabricate than optical sensors. One problem that must be overcome with such sensors is the requirement that the sensing element have access to a sufficient supply of oxygen. The operational principle of these sensors is based on a reaction between glucose and oxygen. Since the concentration of glucose in the body is much greater than that of oxygen, the local supply of oxygen can become depleted unless some provision is made to control the reaction. These issues have been reviewed by Turner and Pickup (Biosensors, 1, 85-115, 1985).
The most favored configuration to date for an electrochemical glucose sensor involves the use of one or two enzymes to catalyze the reaction between glucose and another molecule in order to generate an electrical signal. Typically, glucose oxidase is used to catalyze the reaction between glucose and oxygen to yield gluconic acid and hydrogen peroxide, as follows: ##STR1## The hydrogen peroxide generated may be detected directly or it may be decomposed by a second enzyme, catalase, in which case the sensor will measure oxygen consumption by the reaction involving glucose oxidase.
A desirable feature of a membrane that will be used for glucose sensors is the ratio of oxygen to glucose diffusion constants. It is not enough to have a membrane which has a high oxygen diffusion constant. Silicone has the highest permeability to oxygen of any polymer, but it is useless as a membrane for glucose sensors because it is completely impermeable to glucose. Other membranes might have good permeability to oxygen but too much permeability to glucose. Thus, an ideal polymer system to be used for fabrication of members for a glucose sensor should allow for the preparation of membranes with varying ratios of the diffusion constants so as to be able to match the properties of the membrane to the particular requirements of the sensor.
There remains a need for polymers which can be fabricated into membranes which meet the above requirements and which can have varying diffusion ratios so that the membrane can be tailored to the specific requirements of the sensor.